Since classical interventions using chemotherapy for the treatment of mesothelioma have met with limited success we have elected to approach mesothelioma therapy by targeting tumor differentiation antigens. Our current studies are focused on using immunotherapy directed against mesothelin, a tumor antigen identified in LMB. Mesothelin expression in normal human tissues is limited to mesothelial cells lining the pleura, pericardium and peritoneum but it is highly expressed in several human tumors especially mesothelioma, ovarian, lung and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Having validated mesothelin as a target for cancer therapy our efforts are now focused on exploiting it for mesothelioma therapy using drugs that act by different mechanisms. We are presently evaluating three mesothelin targeted agents in mesothelioma. Two of these agents, CAT-5001 (SS1P) and MORAb-009 are in the clinic and the third agent CRS-207 is about to enter phase I testing. CAT-5001 is a recombinant immunotoxin consisting of an anti-mesothelin Fv linked to a truncated Pseudomonas exotoxin A. We recently completed a phase I clinical trial of CAT-5001 in patients with mesothelin expressing cancers. We established the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics of CAT-5001 and observed anti-tumor activity in a group of heavily pre-treated patients enrolled on this study. Having established the safety and tolerability of CAT-5001 we now plan to evaluate its efficacy in mesothelioma. The strategy we have adopted is to combine CAT-5001 with pemetrexed and cisplatin as front line therapy for patients with unresectable pleural mesothelioma. The rationale for this study is based on our laboratory studies that show marked synergy between CAT-5001 and several chemotherapeutic agents in tumor xenograft models. The second mesothelin targeted agent we are evaluating for mesothelioma therapy is MORAb-009, a chimeric anti-mesothelin monoclonal antibody that was developed as collaboration between LMB and Morphotek Inc. In pre-clinical studies MORAb-009 mediates antibody-dependent cellular cytotoxicity (ADCC) against mesothelin-expressing tumor cells, inhibits mesothelin binding to CA-125 and leads to tumor growth inhibition. We are currently conducting a three institution phase I clinical trial of MORAb-009 in patients with mesothelin-expressing cancers and only patients with mesothelioma have been enrolled on this study at the NCI. Studies by my laboratory have shown that the anti-tumor efficacy of MORAb-009 is markedly increased in combination with gemcitabine and taxol. Based on these results a multi-institutional phase II randomized study of MORAb-009 with gemcitabine versus gemcitabine alone is about to open in advanced pancreatic cancer. In addition, we are in the process of initiating a phase II study of MORAb-009 with chemotherapy in malignant mesothelioma after the completion of the ongoing phase I dose-escalation study. Our group and other investigators have identified mesothelin as a target for vaccine therapy since it is an immunogenic protein that elicits both humoral and cellular immune response in patients. We have also identified the immunogenic epitopes of mesothelin and showed that T-cell lines derived from the native or the agonist mesothelin epitope lyse mesothelin expressing tumor cell lines. We are initiating a phase I clinical trial of CRS-207, a mesothelin tumor vaccine developed by scientists at Cerus Corp. CRS-207 (Lm&#916;actA/&#916;inlB/hMeso) is a tumor vaccine that utilizes a live-attenuated strain of the bacterium Listeria Monocytogenes (Lm) as the vector and encodes human mesothelin. Pre-clinical studies show that CRS-207 elicits human mesothelin-specific CD4+/CD8+ immunity in mice and in cynomolgus monkeys and exhibits therapeutic efficacy in tumor bearing mice. Working with Cerus Corp. we played an important part in protocol development of CRS-207 as it relates to patients with mesothelioma. This clinical trial which will be a 2-3 institution phase I study is currently undergoing scientific review at the NCI. The NCI site will enroll patients with mesothelioma, with the goal of getting safety and efficacy signals that could subsequently lead to a phase II clinical trial in mesothelioma. A translational endpoint of this study is measurement of humoral immune response to mesothelin before and after CRS-207 treatment and will be evaluated using an ELISA developed in our laboratory. Our group has been instrumental in defining mesothelin as a target for cancer therapy as well as developed therapies that we are now evaluating in the clinic. The clinical and translational research done by my group in conjunction with basic laboratory research of the Pastan laboratory has allowed us to take the concept of mesothelin targeting from the bench to the clinic. Besides leading to new treatment options for patients with mesothelioma our research could have implications for the treatment of common cancers such as ovarian, pancreatic and lung adenocarcinomas that highly express mesothelin